Target Information
| Target General Information | Top | |||||
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| Target ID |
T86062
(Former ID: TTDR01072)
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| Target Name |
SREBP cleavage-activating protein (SCAP)
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| Synonyms |
SREBPcleavage-activating protein; SREBP-cleavage activating protein; SCAP
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| Gene Name |
SCAP
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| Target Type |
Literature-reported target
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[1] | ||||
| Function |
Escort protein required for cholesterol as well as lipid homeostasis. Regulates export of the SCAP/SREBF complex from the ER upon low cholesterol. Formation of a ternary complex with INSIG at high sterol concentrations leads to masking of an ER-export signal in SCAP and retention of the complex in the ER. Low sterol concentrations trigger release of INSIG, a conformational change in the SSC domain of SCAP, unmasking of the ER export signal, recruitment into COPII-coated vesicles, transport to the Golgi complex, proteolytic cleavage of SREBF in the Golgi, release of the transcription factor fragmentof SREBF from the membrane, its import into the nucleus and up-regulation of LDLR, INSIG1 and the mevalonate pathway.
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| UniProt ID | ||||||
| Sequence |
MTLTERLREKISRAFYNHGLLCASYPIPIILFTGFCILACCYPLLKLPLPGTGPVEFTTP
VKDYSPPPVDSDRKQGEPTEQPEWYVGAPVAYVQQIFVKSSVFPWHKNLLAVDVFRSPLS RAFQLVEEIRNHVLRDSSGIRSLEELCLQVTDLLPGLRKLRNLLPEHGCLLLSPGNFWQN DWERFHADPDIIGTIHQHEPKTLQTSATLKDLLFGVPGKYSGVSLYTRKRMVSYTITLVF QHYHAKFLGSLRARLMLLHPSPNCSLRAESLVHVHFKEEIGVAELIPLVTTYIILFAYIY FSTRKIDMVKSKWGLALAAVVTVLSSLLMSVGLCTLFGLTPTLNGGEIFPYLVVVIGLEN VLVLTKSVVSTPVDLEVKLRIAQGLSSESWSIMKNMATELGIILIGYFTLVPAIQEFCLF AVVGLVSDFFLQMLFFTTVLSIDIRRMELADLNKRLPPEACLPSAKPVGQPTRYERQLAV RPSTPHTITLQPSSFRNLRLPKRLRVVYFLARTRLAQRLIMAGTVVWIGILVYTDPAGLR NYLAAQVTEQSPLGEGALAPMPVPSGMLPPSHPDPAFSIFPPDAPKLPENQTSPGESPER GGPAEVVHDSPVPEVTWGPEDEELWRKLSFRHWPTLFSYYNITLAKRYISLLPVIPVTLR LNPREALEGRHPQDGRSAWPPPGPIPAGHWEAGPKGPGGVQAHGDVTLYKVAALGLATGI VLVLLLLCLYRVLCPRNYGQLGGGPGRRRRGELPCDDYGYAPPETEIVPLVLRGHLMDIE CLASDGMLLVSCCLAGHVCVWDAQTGDCLTRIPRPGRQRRDSGVGSGLEAQESWERLSDG GKAGPEEPGDSPPLRHRPRGPPPPSLFGDQPDLTCLIDTNFSAQPRSSQPTQPEPRHRAV CGRSRDSPGYDFSCLVQRVYQEEGLAAVCTPALRPPSPGPVLSQAPEDEGGSPEKGSPSL AWAPSAEGSIWSLELQGNLIVVGRSSGRLEVWDAIEGVLCCSSEEVSSGITALVFLDKRI VAARLNGSLDFFSLETHTALSPLQFRGTPGRGSSPASPVYSSSDTVACHLTHTVPCAHQK PITALKAAAGRLVTGSQDHTLRVFRLEDSCCLFTLQGHSGAITTVYIDQTMVLASGGQDG AICLWDVLTGSRVSHVFAHRGDVTSLTCTTSCVISSGLDDLISIWDRSTGIKFYSIQQDL GCGASLGVISDNLLVTGGQGCVSFWDLNYGDLLQTVYLGKNSEAQPARQILVLDNAAIVC NFGSELSLVYVPSVLEKLD Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T59L1E | |||||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: 25-hydroxycholesterol | Ligand Info | |||||
| Structure Description | cryo-EM structure of Scap/Insig complex in the present of 25-hydroxyl cholesterol. | PDB:6M49 | ||||
| Method | Electron microscopy | Resolution | 3.70 Å | Mutation | Yes | [2] |
| PDB Sequence |
ERLREKISRA
14 FYNHGLLCAS24 YPIPIILFTG34 FCILACCYPL44 LKLVAELIPL288 VTTYIILFAY 298 IYFSTRKIDM308 VKSKWGLALA318 AVVTVLSSLL328 MSVGLCTLFG338 LTPTLNGGEI 348 FPYLVVVIGL358 ENVLVLTKSV368 VSTPVDLEVK378 LRIAQGLSSE388 SWSIMKNMAT 398 ELGIILIGYF408 TLVPAIQEFC418 LFAVVGLVSD428 FFLQMLFFTT438 VLSIDIRRME 448 LARLAQRLIM542 AGTVVWIGIL552 VYTDPAGL
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| Ligand Name: Digitonin | Ligand Info | |||||
| Structure Description | Cryo-EM structure of Scap/Insig complex in the present of digitonin. | PDB:7ETW | ||||
| Method | Electron microscopy | Resolution | 4.10 Å | Mutation | Yes | [3] |
| PDB Sequence |
KISRAFYNHG
19 LLCASYPIPI29 ILFTGFCILA39 CCYPLLKLVD70 SDRKQGEPTE80 QPEWYVGAPV 90 AYVQQIFVKS100 SVFPWHKNLL110 AVDVFRSPLS120 RAFQLVEEIR130 NHVLRDSSGI 140 RSLEELCLQV150 TDLLPGLRKL160 RNLLPEHGCL170 LLSPGNFWQN180 DWERFHADPD 190 IIGTIHQHEP200 KTLQTSATLK210 DLLFGVPGKY220 SGVSLYTRKR230 MVSYTITLVF 240 QHYHAKFLGS250 LRARLMLLHP260 SPNCSLRAES270 LVHVHFKEEI280 GVAELIPLVT 290 TYIILFAYIY300 FSTRKIDMVK310 SKWGLALAAV320 VTVLSSLLMS330 VGLCTLFGLT 340 PTLNGGEIFP350 YLVVVIGLEN360 VLVLTKSVVS370 TPVDLEVKLR380 IAQGLSSESW 390 SIMKNMATEL400 GIILIGYFTL410 VPAIQEFCLF420 AVVGLVSDFF430 LQMLFFTTVL 440 SIDIRRMELA450 RLAQRLIMAG523 TVVWIGILVY533 TDPAGLWRKL628 SFRHWPTLFS 638 YYNITLAKRY648 ISLLPVIPVT658 LRL
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Biological Network Descriptors
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| Protein Name | Pfam ID | Percentage of Identity (%) | E value |
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| F-box/WD repeat-containing protein 8 (FBXW8) | 24.060 (32/133) | 2.00E-03 |
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| Degree | 5 | Degree centrality | 5.37E-04 | Betweenness centrality | 1.42E-05 |
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| Closeness centrality | 1.97E-01 | Radiality | 1.34E+01 | Clustering coefficient | 4.00E-01 |
| Neighborhood connectivity | 1.34E+01 | Topological coefficient | 2.85E-01 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| References | Top | |||||
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| REF 1 | Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. | |||||
| REF 2 | A structure of human Scap bound to Insig-2 suggests how their interaction is regulated by sterols. Science. 2021 Mar 5;371(6533):eabb2224. | |||||
| REF 3 | Structural basis for sterol sensing by Scap and Insig. doi:10.1016/j.celrep.2021.109299. | |||||
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